PROJECT SUMMARY/ABSTRACT The principal goal of the Head and Neck Cancer Program (HNP) at MD Anderson is to improve prevention, rates of cure, and quality of life for patients with head and neck cancers. The program is led by Jeffrey N. Myers, MD, PhD, a surgical oncologist and physician-scientist; Maura L. Gillison, MD, PhD, a physician-scientist; and Steven I. Sherman, MD, an endocrinologist and clinical investigator. The HNP includes 69 members (34 primary, 27 associate, 8 adjunct) from 16 departments. The program is organized around 3 major themes: 1) genomics and molecular precision therapeutics; 2) translational immunobiology and immunotherapy; and 3) treatment toxicity and quality of life. Each theme is addressed by a specific aim. Aim 1: To enhance patient outcomes through the study of genomic alterations in cancers in order to identify pathogenic drivers, novel therapeutic targets, and mechanisms of resistance. Aim 2: To perform translational studies that identify therapeutic targets in the immune microenvironment and predictors of response and resistance to immunotherapy. Aim 3: To decrease the symptom burden and adverse impact of head and neck cancer treatments on patient quality of life through treatment de-intensification, rehabilitative strategies, and research on symptom control and functional outcome. The annual direct peer-reviewed funding of the HNP totals $3.1M, including a U01 with $792,088 (25%) from NCI grants and $1.9M (61%) from NIDCR, whose Oral and Pharyngeal Cancer Branch funds a large portfolio of grants in this area. Since the last submission, the program has published 879 papers: 522 (59%) represent intra-programmatic collaborations, 258 (29%) represent inter-programmatic collaborations, and 528 (60%) represent inter-institutional collaborations. Thirty-four percent of articles appeared in journals with IF >5 and 9% in journals with IF>10, including papers in the N Engl J Med, Proc Natl Acad Sci USA, and Cancer Discov. Program members use 14 shared resources. During the past grant period, members of the HNP have made critical contributions in the integrative genomics of oral cancer; the science of immunology and vaccines in head and neck cancer (HNC); molecular targeting for oral cancer prevention; and molecular targeting of treatment of aggressive thyroid cancers. Another important advance by HNP members has been to help devise a new American Joint Commission on Cancer (AJCC) staging system for oropharyngeal cancer. HNP members were also major contributors to The Cancer Genome Atlas (TCGA) and played key leadership roles in the American Head and Neck Society, NRG Head and Neck Cancer Steering Committee.